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- EMDB-24463: Cryo-EM structure of human rod CNGA1/B1 channel in L-cis-Diltiaze... -

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Basic information

Entry
Database: EMDB / ID: EMD-24463
TitleCryo-EM structure of human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state
Map data
Sample
  • Complex: human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state
    • Protein or peptide: cGMP-gated cation channel alpha-1
    • Protein or peptide: Cyclic nucleotide-gated cation channel beta-1
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: (2R,3R)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate
Keywordsion channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


olfactory nerve maturation / non-motile cilium membrane / detection of chemical stimulus involved in sensory perception of smell / photoreceptor cell outer segment organization / protein localization to organelle / intracellular cyclic nucleotide activated cation channel complex / detection of light stimulus involved in visual perception / intracellularly cGMP-activated cation channel activity / ion channel modulating, G protein-coupled receptor signaling pathway / response to odorant ...olfactory nerve maturation / non-motile cilium membrane / detection of chemical stimulus involved in sensory perception of smell / photoreceptor cell outer segment organization / protein localization to organelle / intracellular cyclic nucleotide activated cation channel complex / detection of light stimulus involved in visual perception / intracellularly cGMP-activated cation channel activity / ion channel modulating, G protein-coupled receptor signaling pathway / response to odorant / VxPx cargo-targeting to cilium / rod photoreceptor outer segment / intracellularly cAMP-activated cation channel activity / Golgi-associated vesicle membrane / photoreceptor cell maintenance / retina homeostasis / sodium channel activity / ciliary membrane / photoreceptor outer segment membrane / sodium ion transport / monoatomic cation transmembrane transport / monoatomic cation transport / phototransduction / membrane depolarization / cGMP binding / ligand-gated monoatomic ion channel activity / photoreceptor outer segment / transmembrane transporter complex / cAMP binding / regulation of cytosolic calcium ion concentration / visual perception / potassium ion transport / Olfactory Signaling Pathway / calcium channel activity / Activation of the phototransduction cascade / terminal bouton / calcium ion transport / Inactivation, recovery and regulation of the phototransduction cascade / sensory perception of smell / protein-containing complex binding / positive regulation of gene expression / plasma membrane
Similarity search - Function
Cyclic nucleotide-gated channel, C-terminal leucine zipper domain / C-terminal leucine zipper domain of cyclic nucleotide-gated channels / : / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain ...Cyclic nucleotide-gated channel, C-terminal leucine zipper domain / C-terminal leucine zipper domain of cyclic nucleotide-gated channels / : / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / RmlC-like jelly roll fold / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Cyclic nucleotide-gated channel alpha-1 / Cyclic nucleotide-gated channel beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsXue J / Han Y
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140892 United States
Welch FoundationI-1578 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Neuron / Year: 2022
Title: Structural mechanisms of assembly, permeation, gating, and pharmacology of native human rod CNG channel.
Authors: Jing Xue / Yan Han / Weizhong Zeng / Youxing Jiang /
Abstract: Mammalian cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cGMP or cAMP and play essential roles in the signal transduction of the visual and olfactory sensory ...Mammalian cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cGMP or cAMP and play essential roles in the signal transduction of the visual and olfactory sensory systems. CNGA1, the principal component of the CNG channel from rod photoreceptors, can by itself form a functional homotetrameric channel and has been used as the model system in the majority of rod CNG studies. However, the native rod CNG functions as a heterotetramer consisting of three A1 and one B1 subunits and exhibits different functional properties than the CNGA1 homomer. Here we present the functional analysis of human rod CNGA1/B1 heterotetramer and its cryo-EM structures in apo, cGMP-bound, cAMP-bound, and L-cis-Diltiazem-blocked states. These structures, with resolution ranging from 2.6 to 3.3 Å, elucidate the structural mechanisms underlying the 3:1 subunit stoichiometry, the asymmetrical gating upon cGMP activation, and the unique pharmacological property of the native rod CNG channel.
History
DepositionJul 17, 2021-
Header (metadata) releaseNov 3, 2021-
Map releaseNov 3, 2021-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7rhj
  • Surface level: 0.025
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24463.png

Downloads & links

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Map

FileDownload / File: emd_24463.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 288 pix.
= 241.632 Å		0.84 Å/pix.
x 288 pix.
= 241.632 Å		0.84 Å/pix.
x 288 pix.
= 241.632 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.839 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.023 / Movie #1: 0.025
Minimum - Maximum-0.069945455 - 0.13793729
Average (Standard dev.)0.00040095823 (±0.005607035)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 241.63199 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8390.8390.839
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z241.632241.632241.632
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.0700.1380.000

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Supplemental data

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Sample components

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Entire : human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state

EntireName: human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state
Components
  • Complex: human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state
    • Protein or peptide: cGMP-gated cation channel alpha-1
    • Protein or peptide: Cyclic nucleotide-gated cation channel beta-1
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: (2R,3R)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate

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Supramolecule #1: human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state

SupramoleculeName: human rod CNGA1/B1 channel in L-cis-Diltiazem-blocked open state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: cGMP-gated cation channel alpha-1

MacromoleculeName: cGMP-gated cation channel alpha-1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.650434 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKG GSASKDKKEE EKKEVVVIDP SGNTYYNWLF CITLPVMYNW TMVIARACFD ELQSDYLEYW LILDYVSDIV YLIDMFVRT RTGYLEQGLL VKEELKLINK YKSNLQFKLD VLSLIPTDLL YFKLGWNYPE IRLNRLLRFS RMFEFFQRTE T RTNYPNIF ...String:
MDYKDDDDKG GSASKDKKEE EKKEVVVIDP SGNTYYNWLF CITLPVMYNW TMVIARACFD ELQSDYLEYW LILDYVSDIV YLIDMFVRT RTGYLEQGLL VKEELKLINK YKSNLQFKLD VLSLIPTDLL YFKLGWNYPE IRLNRLLRFS RMFEFFQRTE T RTNYPNIF RISNLVMYIV IIIHWNACVF YSISKAIGFG NDTWVYPDIN DPEFGRLARK YVYSLYWSTL TLTTIGETPP PV RDSEYVF VVVDFLIGVL IFATIVGNIG SMISNMNAAR AEFQARIDAI KQYMHFRNVS KDMEKRVIKW FDYLWTNKKT VDE KEVLKY LPDKLRAEIA INVHLDTLKK VRIFADCEAG LLVELVLKLQ PQVYSPGDYI CKKGDIGREM YIIKEGKLAV VADD GVTQF VVLSDGSYFG EISILNIKGS KAGNRRTANI KSIGYSDLFC LSKDDLMEAL TEYPDAKTML EEKGKQILMK DGLLD LNIA NAGSDPKDLE EKVTRMEGSV DLLQTRFARI LAEYESMQQK LKQRLTKVEK FLKPLIDTEF SSIEGPGAES GPIDST

UniProtKB: Cyclic nucleotide-gated channel alpha-1

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Macromolecule #2: Cyclic nucleotide-gated cation channel beta-1

MacromoleculeName: Cyclic nucleotide-gated cation channel beta-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.039305 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKG GSASSGVPAT KQHPEVQVED TDADSCPLMA EENPPSTVLP PPSPAKSDTL IVPSSASGTH RKKLPSEDDE AEELKALSP AESPVVAWSD PTTPKDTDGQ DRAASTASTN SAIINDRLQE LVKLFKERTE KVKEKLIDPD VTSDEESPKP S PAKKAPEP ...String:
MDYKDDDDKG GSASSGVPAT KQHPEVQVED TDADSCPLMA EENPPSTVLP PPSPAKSDTL IVPSSASGTH RKKLPSEDDE AEELKALSP AESPVVAWSD PTTPKDTDGQ DRAASTASTN SAIINDRLQE LVKLFKERTE KVKEKLIDPD VTSDEESPKP S PAKKAPEP APDTKPAEAE PVEEEHYCDM LCCKFKHRPW KKYQFPQSID PLTNLMYVLW LFFVVMAWNW NCWLIPVRWA FP YQTPDNI HHWLLMDYLC DLIYFLDITV FQTRLQFVRG GDIITDKKDM RNNYLKSRRF KMDLLSLLPL DFLYLKVGVN PLL RLPRCL KYMAFFEFNS RLESILSKAY VYRVIRTTAY LLYSLHLNSC LYYWASAYQG LGSTHWVYDG VGNSYIRCYY FAVK TLITI GGLPDPKTLF EIVFQLLNYF TGVFAFSVMI GQMRDVVGAA TAGQTYYRSC MDSTVKYMNF YKIPKSVQNR VKTWY EYTW HSQGMLDESE LMVQLPDKMR LDLAIDVNYN IVSKVALFQG CDRQMIFDML KRLRSVVYLP NDYVCKKGEI GREMYI IQA GQVQVLGGPD GKSVLVTLKA GSVFGEISLL AVGGGNRRTA NVVAHGFTNL FILDKKDLNE ILVHYPESQK LLRKKAR RM LRSNNKPKEE KSVLILPPRA GTPKLFNAAL AMTGKMGGKG AKGGKLAHLR ARLKELAALE AAAKQQELVE QAKSSQDV K GEEGSAAPDQ HTHPKEAATD PPAPRTPPEP PGSPPSSPPP ASLGRPEGEE EGPAEPEEHS VRICMSPGPE PGEQILSVK MPEEREEKAE

UniProtKB: Cyclic nucleotide-gated channel beta-1

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Macromolecule #3: CYCLIC GUANOSINE MONOPHOSPHATE

MacromoleculeName: CYCLIC GUANOSINE MONOPHOSPHATE / type: ligand / ID: 3 / Number of copies: 4 / Formula: PCG
Molecular weightTheoretical: 345.205 Da
Chemical component information

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

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Macromolecule #4: (2R,3R)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,...

MacromoleculeName: (2R,3R)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate
type: ligand / ID: 4 / Number of copies: 1 / Formula: 5H0
Molecular weightTheoretical: 414.518 Da
Chemical component information

ChemComp-5H0:
(2R,3R)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 187429
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: RANDOM ASSIGNMENT

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